Interaction between Ras and Src clones causes interdependent tumor malignancy via Notch signaling in Drosophila

A review of the methods used to induce cancer in invertebrates to study its effects on the evolution of species and ecosystem functioning

“…Indeed tumours can be induced in the intestine by modifying the APC and Ras pathways to create APC–Ras clones in adults (Martorell et al, 2014) or in larvae's eyes by altering the scrib 1 /Ras v12 pathway (Pagliarini & Xu, 2003). Similarly, the concomitant activation of both the Ras v12 and Scr pathways, or the overexpression of the Ret receptor tyrosine kinase can be used to induce malignant tumours in the eye (Enomoto et al, 2021; Read et al, 2005). In parallel with activating oncogenes, RNA interference can be employed to downregulate genes, thus facilitating the apparition of tumours (e.g.…”

“…The duration of exposure (when relevant), the sample size of the experiments and the prevalence of cancer observed are provided for each group. Source: Planarians: (Foster, 1963;Hall et al, 1986;Plusquin et al, 2012;Schaeffer, 1993;Van Roten et al, 2018;Voura et al, 2017); Hydra: (Domazet-Lošo et al, 2014;Rathje et al, 2020), Justine Boutry personal communication; Bivalves (Gardner et al, 1991(Gardner et al, , 1992House, 1997;Khudoley & Syrenko, 1978;Mateo et al, 2015;Walker et al, 2009); Drosophila: (Enciso et al, 2018;Enomoto et al, 2021;Enzmann, 1951;Hartung, 1942;Martorell et al, 2014;Pagliarini & Xu, 2003;Read et al, 2005;Shu et al, 2017;Willecke et al, 2011). Photo credits: Planarian, Eduard Solà, modified; Bivalve, Ecomare/Oscar Bos, modified; drosophila, Sanjay Acharya, modified (under CC BY-SA 4.0 License, https://creat iveco mmons.org/licen ses/bysa/4.0/legal code); Hydra, Jordan Meliani, modified planarians can be induced by exposing them to heavy metals such as cadmium (Schaeffer, 1993;Voura et al, 2017) or to a relatively large range of aromatic hydrocarbon molecules (Foster, 1963;Hoshina & Teshirogi, 1991;Schaeffer, 1993).…”

The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in Drosophila melanogaster

“…Accordingly, the eye defects resulting from an induction of the pro-apoptotic genes p53 , hid , rpr and grim were considerably ameliorated by the concurrent EP555 overexpression ( Figure 3 ). Notch signaling activity is instrumental to the control of growth and cell death [ 2 , 61 , 62 , 63 , 64 ]. Accordingly, a Notch agonist may be expected to counteract pro-apoptotic gene activity, for example by promoting cell proliferation.…”

Cell-cell interactions that drive tumorigenesis in Drosophila

“…Given that Src activity and expression are increased in cancers[ 54 ], Src-activated cells may evade cell competition during cancer progression. Interestingly, it has been shown that Src cells transform into malignant tumours when Ras is activated in neighbouring cells in Drosophila imaginal disc [ 59 ] ( Figure 2c ). Ras V12 and Src clones increase the cell surface ligand Delta and its receptor Notch, respectively, and thus Delta-Notch interaction occurs at the boundary between these clones.…”

“…Ras V12 and Src clones increase the cell surface ligand Delta and its receptor Notch, respectively, and thus Delta-Notch interaction occurs at the boundary between these clones. Activated Notch signalling in Src clones induces the transcriptional repressor Zfh1 (a ZEB1 homolog), which transforms Src cells into malignant tumours by downregulating shotgun ( shg, an E-cadherin homolog) and a pro-apoptotic gene hid [ 59 ] ( Figure 2c ). Simultaneously, Notch signalling in Src cells induces Upd, which activates JAK-STAT signalling in neighbouring Ras V12 cells.…”